Supporting activities of daily living

ABSTRACT

The invention provides a method for supporting operational activities in daily living by providing a combination of (a) long-chain polyunsaturated fatty acids, particularly DHA and/or EPA, and (b) nucleosides or nucleotides, particularly uridine or its equivalent. The operational activities comprise eating; walking; toileting; bathing; grooming; dressing; use of communication equipment; making conversations; keeping appointments; use of household appliances; cleaning dishes; preparation of meal or drink; writing; reading; independent housekeeping; transportation and shopping.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a Continuation of U.S. application Ser. No.12/666,621, filed May 11, 2010, now U.S. Pat. No. 8,361,989, which isthe National Stage application of International Application No.PCT/NL2008/050406, filed Jun. 20, 2008, which claims the benefit andpriority of International Application No. PCT/NL2007/050307, filed Jun.26, 2007. The foregoing applications are incorporated by referenceherein in their entirety.

FIELD OF THE INVENTION

The invention relates to preparations, which comprise long chainpolyunsaturated fatty acids and/or nucleotides or their equivalents, andwhich support the activities of daily living.

BACKGROUND OF THE INVENTION

Neuropathies or neurological problems may find their cause in aging, inprevalent pathologies in the brain, like those associated with theformation of plaques or neurofibrillary tangles in the brain. In manyoccasions neuropathies or neurological problems lead to a loss ofindependency and a need to provide extra care or a need to move theperson to a nursing home or the like, in order to ensure a sustainablelife of these persons.

WO02/088159 describes the neuroprotective effect of a lipoic acidderivative of uridine. WO2006/031683 relates to methods of improvingcognitive and neurological functions and increasing synthesis andrelease of neurotransmitters and membrane synthesis by neural cells andbrain cells, comprising administering a composition comprising auridine. WO2007/004685 describes a composition containing DHA andarachidonic acid that has an activity of ameliorating reduced higherbrain functions resulting from organic brain lesions. WO2007/004689discloses a composition having an activity of ameliorating the reducedamount of diurnal activity and/or depressive symptoms, comprisingarachidonic acid and/or a compound having arachidonic acid as aconstituent fatty acid. US2007/0004670 describes methods of improvingmemory, learning, cognition, synaptic transmission and synthesis andrelease of neurotransmitters and increasing brain phospholipid levels ina subject. WO2006/127620 discloses a composition comprising DHA and UMPfor the treatment of a subject with a memory disorder, learningproblems, or a neurological disorder, such as an Alzheimer patient.

Wurtman et al., Brain Research 2006, 1088(1), 83-92 disclose acombination of choline, UMP and DHA as being able to enhance thequantity of synaptic proteins and phospholipids in gerbil brains andbeing potentially useful in treating Alzheimer's disease. EP1 656 839discloses a composition for feeding infants of a mother who sufferedfrom metabolic disorders during pregnancy, comprising inter alia DHA,EPA, uridine and choline. WO2007/058538 discloses a composition fortreating a number of diseases such as AIDS, diarrhoea, etc. wherein saidcomposition comprises inter alia a) DHA and EPA, b) uridine and c)choline. EP1 666 092 discloses a combination of DHA and uridine for thetreatment of Alzheimer, depression and/or diabetes. JP3-576318 B2discloses a nutritional composition for favourable growth andmaintenance of healthy conditions comprising DHA and UMP. WO03/041701discloses a composition comprising DHA, EPA, choline, methionine,vitamin B6, folic acid, zinc, magnesium and UMP as alternative fornucleobases for the treatment of Parkinson's disease, epilepsy,schizophrenia, paranoia, depression, sleep disorders, psychoses,dementia, ADHA, impaired memory function, chronic fatigue syndrome andmotor disorders.

None of the above documents discloses the improvement of activities ofdaily living, as defined in this invention. Moreover, it is imperativeto understand that the invention is not concerned with the treatment ofAlzheimer's disease or dementia itself, but with the treatment ofpersons suffering from Alzheimer's disease, dementia and/or elderly.

SUMMARY OF THE INVENTION

The present inventors found that the administration of the presentcomposition improves activities wherein the (i) operational activitiesand the executive brain functions play an important role (i.e. theinstrumental and/or basic activities of daily living). Such activitiesinclude many activities that take place throughout the day, particularlyhousekeeping, personal hygiene practices and meal preparation. Thisfinding particularly enables persons that are suffering from difficultyin performing such activities (e.g. humans suffering from Alzheimer'sdisease, dementia and/or non-dementing or dementing elderly) to prolongan independent way of living. The improvement in ability to perform theinstrumental and/or basic activities of daily living is often consideredmore important than improving memory and/or cognitive function.

This finding is particularly unexpected as the coordination of thesecomplex activities of daily living is coordinated by different parts ofthe brain, i.e. the operational parts of the activities are (mainly)coordinated by the motor cortex, the executive (e.g. planning) parts ofthe activities of daily living are (mainly) coordinated by theprefrontal cortex, while memory functions are (mainly) coordinated bythe hippocampus and temporal cortex. Experimental results showed thatadministration of the present composition to subjects suffering fromimpaired brain functions (particularly Alzheimer's disease) restored theactivities, to near normal levels. Hence, the present inventors foundthat the present composition has an important stimulatory effect on theinstrumental and/or basic activities of daily living, particularly inhumans suffering from Alzheimer's disease. The present compositionsupports and enable those complex activities where initiation, planningand effective operation performance play a role.

In a further aspect, the present inventors found, in addition to theabove, that the present composition for supporting the activities ofdaily living advantageously comprises folic acid, vitamin B12 and/orvitamin B6, preferably in relatively high dosages. It was found thatthese vitamins can be advantageously included in the present invention.The administration of the B vitamins was found to decrease locomotoractivity during the resting period, hence ensuring a good rest duringthe night. Hence, the present composition, when including B-vitaminsadvantageously supports the present activities of daily living, whileproviding a good resting period.

The present finding enables a solution for an important problem forhumans suffering from Alzheimer's, dementia and/or aging (i.e. theelderly). Many subjects fear the time that they become dependent on thehelp and support from others when desiring to perform activities ofdaily living. Hence, for these subjects it is particularly desirable toextend the period of independence. The present inventors solved thisproblem by providing a (nutritional) composition that is easy to ingest,and enables a prolonged capacity to perform the relatively complexactivities of daily living.

In particular, the present invention relates to improvements inindependent performance of activities wherein the operational aspect hasa dominant role. The present invention particularly relates toimprovements in independent performance of the following activities:coordination of movements, particularly when eating or drinking;grasping goods; putting objects on a desired location/position; makingrapid movements; walking; maintaining balance in body position; doingthe laundry; doing the dishes.

In a further aspect the present invention relates to improvements inindependent performance of activities wherein the operational aspect hasa main role, in addition to other higher brain functions. The presentinvention particularly relates to improvements in independentperformance of the following activities: using communication equipment,especially telephone; using household appliances, especially television;personal hygiene practices, particularly cutting nails, doing hairproperly or apply shaving practices; dressing, preparing a meal,shopping, travelling.

It was found that particularly the administration of a preparation thatcomprises DHA and uridine results in the desired improvements. It isconsidered particularly advantageous to co-administer with the DHAand/or uridine at least one of vitamin B6, vitamin B12 and/or folicacid. Inclusion of these vitamins improves the effects of theadministration of DHA and/or nucleotide. Further improvements can beachieved by co-administration of phospholipids. Without wishing to bebound by theory, the present inventors believe that the phospholipidsenable effective membrane function, further improving effectiveness ofthe present composition in it's support for daily living activities.

At the same time, the present product preferably is formulated so thatit has a relatively low impact on appetite and consumption patterns ofother food, and is easy to consume. It preferably does not comprise herbextracts, which may be varying in quality, and under normalcircumstances are difficult to include in stable sterilized liquidproducts and may comprise components which have a badly definedbiological action.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows relative locomotor activity in abeta-infused and “sham”rats on diet A (control) versus diet B (experiment).

FIG. 2 shows the ADCS-ADL score over a 12 weeks intervention period ofAlzheimer's patients treated with a product according to Example 2 vs acontrol.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides the use of a composition comprising (a)DHA and/or EPA, and (b) uridine or its equivalent, in the manufacture ofa composition for supporting activities in daily living. Alternativelythe present invention provides a method for supporting activities indaily living, said method comprising administering to a patient(particularly a patient suffering from Alzheimer's disease) acomposition comprising (a) DHA and/or EPA, and (b) uridine or itsequivalent.

In a further aspect the present invention provides a liquid compositioncomprising per 100 ml, 0.2-2 gram uridine of an uridine equivalent;0.5-5 g DHA; 0.5-10 g protein; 2-20 g carbohydrates; 0.5-15 microgramvitamin B12; 50-1000 microgram folic acid and 0.1-10 mg vitamin B6,wherein the composition has a viscosity of 1-40 mPas measured at a shearrate of 100 per sec at 20° C.; an osmolality of 300 to 800 mOsm/kg and acaloric density between 0.2 and 3 kcal/ml.

LC-PUFA

The present invention comprises the use of long chain polyunsaturatedfatty acids (LCP), preferably at least one LCP selected fromdocosahexaenoic acid (22:6 ω-3; DHA), docosapentaenoic acid (22:5 ω-3;DPA) and eicosapentaenoic acid (20:5 ω-3; EPA). Preferably the presentcomposition contains at least DHA, preferably DHA and EPA. Morepreferably the composition contains DHA and at least one precursor ofDHA selected from EPA and DPA, more preferably the present compositioncomprises DHA, DPA and EPA. The inventors recognized that only part ofthe DHA incorporated in the brain is from orally ingested DHA. Animportant part of the DHA incorporated in the brain is derived fromconversion of DPA to DHA in the brain. In a further aspect the presentcomposition preferably contains a significant amount of EPA. EPA isconverted to DPA (ω-3), increasing subsequent conversion of DPA (ω-3) toDHA in the brain. Hence, the present composition preferably alsocontains a significant amount of EPA, so to further stimulate in-vivoDHA formation.

The LCP is preferably provided as triglycerides, diglycerides,monoglycerides, free fatty acids or their salts or esters,phospholipids, lysophospholipids, glycerol ethers, lipoproteins,ceramides, glycolipids or combinations thereof. Preferably, the presentcomposition comprises at least DHA in triglyceride form.

The present method preferably comprises the administration of 400-5000mg (DHA+EPA) per day, more preferably 500-3000 mg per day. Theproportion of (DHA+EPA) of the total fatty acids is preferably 5-50 wt.%, more preferably 10-45 wt. %, most preferably 15-40 wt. %. The presentmethod preferably comprises the administration of DHA, preferably in anamount of 300-4000 mg per day, more preferably 500-2500 mg per day. Thepresent method preferably comprises the administration of DHA,preferably a composition comprising 300-4000 mg DHA per 100 ml day, morepreferably 500-2500 mg DHA per 100 ml. The present compositionpreferably comprises 1-40 wt. % DHA based on total fatty acids,preferably 3-36 wt. % DHA based on total fatty acids, more preferably10-30 wt. % DHA based on total fatty acids. The present compositionpreferably comprises 0.5-20 wt. % EPA based on total fatty acids,preferably 2-10 wt. % EPA based on total fatty acids, more preferably5-10 wt. % EPA based on total fatty acids. The ratio of the weights ofDHA to the sum of EPA and DPA (ω-3) is preferably larger than 1.0, morepreferably 1.2-10, most preferably 2-8. The above-mentioned ratios andamounts take into account and optimise several aspects, including taste(too high LCP levels reduce taste, resulting in a reduced compliance),balance between DHA and precursors thereof to ensure optimaleffectiveness in relation to maximum dosage and possibility of productformulations such as liquid form, bar or capsule.

The present composition preferably contains a very low amount ofarachidonic acid (AA; 20:4 ω-6). Arachidonic acid is believed tocounteract the effects of the present composition. The subjects of thepresent method normally ingest sufficient (precursors of) AA, and anexcess daily dosage may stimulate inflammatory responses, inhibitingactivities of daily living. Preferably the weight ratio DHA/AA in thepresent composition is at least 5, preferably at least 10, morepreferably at least 15, up to e.g. 60 or up to 30. The present methodpreferably comprises the administration of a composition comprising lessthan 5 wt. % arachidonic acid based on total fatty acids, morepreferably below 2.5 wt. %, e.g. down to 0.5 wt. %. The ratio ω-6/ω-3fatty acids (C 18 and higher) in the present product is preferably below0.5, more preferably below 0.2, e.g. down to 0.05 or to 0.1. The ratioω-6/ω-3 fatty acids (C 20 and higher) in the present product ispreferably below 0.3, more preferably below 0.15, e.g. down to 0.03 orto 0.06.

The present composition preferably contains at least one oil selectedfrom fish oil, algal oil and eggs lipids. Preferably the presentcomposition contains fish oil comprising DHA, EPA and preferably DPA.

Saturated and Monounsaturated Fatty Acids

The present composition preferably comprises saturated and/ormono-unsaturated fatty acids. The amount of saturated fatty acids ispreferably 6-60 wt. % based on total fatty acids, preferably 12-40 wt.%, more preferably 20-40 wt. % based on total fatty acids. In particularthe amount of C14:0 (myristic acid) +C16:0 (palmitic acid) is preferably5-50 wt. %, preferably 8-36, more preferably 15-30 wt. % based on totalfatty acids. The total amount of monounsaturated fatty acids, such asoleic acid and palmitoleic acid, is preferably between 5 and 40 wt. %,more preferably between 15 and 30 wt. %. Including of the saturatedand/or monounsaturated fatty acids provides an energy source, improvingthe present activities of daily living.

Phospholipids

Preferably, the present composition preferably comprises phospholipids,preferably 0.1-50 wt. % phospholipids based on total weight of lipids,more preferably 0.5-20 wt. %, more preferably between 1 and 5 wt. %based on total weight of lipids. The total amount of lipids ispreferably between 10 and 30 wt. % on dry matter, and/or between 2 and 6g lipid per 100 ml for a liquid composition. Inclusion of phospholipidsbeneficially improves membrane function, thereby enabling an improvedfunctioning of the different parts of the brain that play a (main) rolein activities of daily living. Furthermore, the phospholipids improvestability of the present product.

Folic Acid, Vitamin B12 and/or Vitamin B6

The present composition preferably contain folic acid, vitamin B12and/or vitamin B6, particularly in (relatively) high dosages. Inclusionof these vitamins advantageously provides the combination of support andenablement of activities of daily living, while providing a reducedlocomotor activity during the resting period. Further advantage ofco-administration of folic acid, vitamin B12 and/or vitamin B6 is thatis relief's patients of deficiencies in these vitamins. Preferably thepresent composition comprises at least two selected from the groupconsisting of folic acid, vitamin B12 and/or vitamin B6. More preferablythe present composition comprises folic acid, vitamin B12 and vitaminB6.

The present composition preferably comprises 50-1000 microgram folicacid per 100 g liquid product, more preferably 150-750 microgram folicacid per 100 g liquid product, more preferably 200-500 microgram folicacid per 100 g liquid product. The present method preferably comprisesthe administration 50-1000 microgram folic acid per day, more preferably150-750 microgram folic acid per day, more preferably 200-500 microgramfolic acid per day. The present composition preferably comprises 0.5-15microgram vitamin B12 per 100 g liquid product, more preferably 1-10microgram vitamin B12 per 100 g liquid product, more preferably 1.5-5microgram vitamin B12 per 100 g liquid product. The present methodpreferably comprises the administration 0.5-15 microgram vitamin B12 perday, more preferably 1-10 microgram vitamin B12 per day, more preferably1.5-5 microgram vitamin B12 per day. The present composition preferablycomprises 0.1-10 mg vitamin B6 per 100 g liquid product, more preferably0.4-5 mg vitamin B6 per 100 g liquid product, more preferably 0.6-5 mgvitamin B6 per 100 g liquid product. The present method preferablycomprises the administration 0.1-10 microgram vitamin B6 per day, morepreferably 0.5-5 mg vitamin B6 per day, more preferably 0.75-5 mgvitamin B6 per day.

Nucleotides

The present composition preferably comprises uridine and/or anequivalent thereof, preferably at least one uridine or an equivalentthereof selected from the group consisting of uridine (i.e. ribosyluracil), deoxyuridine (deoxyribosyl uracil), uridine phosphates (UMP,dUMP, UDP, UTP), nucleobase uracil and acylated uridine derivatives.Preferably the present composition comprises one or more uridinephosphate selected from the group consisting of uridine monophosphate(UMP), uridine diphosphate (UDP and uridine triphosphate (UTP). Mostpreferably the present composition comprises UMP, as UMP is mostefficiently being taken up by the body. Preferably at least 50 wt. % ofthe uridine in the present composition is provided by UMP, morepreferably at least 75 wt. %, most preferably at least 95 wt. %. Thepresent method preferably comprises the administration of uridine (thecumulative amount of uridine, deoxyuridine, uridine phosphates,nucleobase uracil and acylated uridine derivatives) in an amount of0.08-3 g per day, preferably 0.1-2 g per day, more preferably 0.2-1 gper day.

Preferably the present composition comprises uridine phosphate,preferably uridine monophosphate (UMP). The UMP very efficiently takenup by the body. Hence, inclusion of UMP in the present product enables ahigh effectively at the lowest dosage and/or the administration of a lowvolume to the subject. Preferably the weight ratio of uridine tocytidine is larger that 1.0, more preferably 2.0, most preferably morethan 5.0. The term uridine as used herein relates to uridine and/orequivalents thereof. The term cytidine as used herein relates tocytidine and/or equivalent thereof. Although cytidine is a precursor ofuridine, which passes the blood brain barrier, it is more efficient andeffective to include uridine in the present composition.

The present method preferably comprises the administration of uridinemonophosphate (UMP) in an amount of 0.08-3 g per day, preferably 0.1-2 gper day, more preferably 0.2-1 g per day. The present method preferablycomprises the administration of a composition comprising uridine in anamount of 0.08-3 g UMP per 100 ml liquid product, preferably 0.1-2 g UMPper 100 ml liquid product, more preferably 0.2-1 g per 100 ml liquidproduct. Preferably 1-37.5 mg UMP per kilogram body weight isadministered per day. The required dosages of the equivalents on aweight base can be calculated from the dose for UMP by taking equimolaramounts using the molecular weight of the equivalent and of UMP, thelatter being 324 Dalton. The amount of nucleotides or nucleosides andderivatives is preferably 3-115 μmol, preferably 5-35 μmol per kg bodyweight per day, or 0.25 to 9 mmol, preferably 0.3-6, most preferably0.45-2.8 mmol per day.

Uridine derivatives like UDP, which is readily formed from dietetic UMP,appear to be important for transport of glycoproteins and glycolipidswithin the cell and availability thereof in the cytosol and plasmamembrane.

In a further preferred embodiment the present composition preferablydoes not contain high amounts of other nucleotides. Hence, preferablythe weight ratio adenosine/uridine in the present composition is below0.1, more preferably below 0.01, most preferably 0. Preferably theweight ratio guanosine/uridine in the present composition is below 0.1,more preferably below 0.01, most preferably 0. Preferably the weightratio inosine/uridine in the present composition is below 0.1, morepreferably below 0.01, most preferably 0.

Combination of Uridine and LCP

It was found by the inventors that the nucleotide equivalents asdefined, and in particular the uridine sources as defined are importantto support and/or enhance the effect of the lipid fractions as definedabove on activities of daily living. The present combination,particularly of (i) uridine and (ii) DHA and/or EPA is surprisinglyeffective. On a biochemical level this may be observed by an improvementof ceramide metabolism in membranes and in particular an increase inglycolipids at the expense of the presence of simple ceramides.

Methyl Donors

Preferably the present composition contains methyl donors. Methyl donorsare those food grade compounds which are capable of providing a methyl,methylene or formyl group when administered to a human individual invivo. The methyl donor included in the present composition is preferablyselected from the group consisting of serine, methionine, choline,betaine, dimethylglycine and sarcosine and derivatives thereof.Preferably the present composition contains choline and/orphosphatidylcholine. The present method preferably comprises theadministration of more than 50 mg choline per day, preferably 80-2000 mgcholine per day, more preferably 120-1000 mg choline per day, mostpreferably 150-600 mg choline per day. The present compositionpreferably comprises 50 mg to 3 gram choline per 100 ml of the presentliquid formula, preferably 200 mg-1000 mg choline/100 ml. The methyldonor (particularly choline) is an important precursor of the brainmembrane and thereby enables a improved functioning of the brain areainvolved in supporting activities of daily living. In a particularlypreferred embodiment the present composition comprises phospholipids andcholine. It was found that the administration of phospholipids withcholine results in maintenance of high choline level. As choline is animportant precursor of muscle neurotransmitters, high choline levels (asa result of administration of phospholipids) support of daily livingactivities.

Minerals & Trace Elements

The present composition can be further improved by including one or moreminerals. Preferably the present composition comprises at least onemineral selected from zinc, magnesium, copper, manganese and molybdenum.Preferably the present composition comprises manganese and molybdenum.

Manganese

Inclusion of manganese in a diet is important for improving membranefunction of cells, in particular the membrane function of nerve cells.Especially those persons that are malnourished or have an inherited ormetabolic disorder involving imparted metabolic capacity for producingsphingomyelin and/or related compounds like sulfatides and glycosylatedceramides, benefit from inclusion of the mineral fraction.

The amount of manganese administered per day is preferably more than 0.1mg, more preferably 0.1-1 mg. Preferably the present method comprisesthe administration of a (liquid) composition comprising 0.05 to 2 mgmanganese per 100 ml, preferably 0.1-1 mg manganese per 100 ml.

Molybdenum

Additional molybdenum is strongly preferred to allow proper functioningof the cofactors, which appears important for creating a propercomposition of the membranes, e.g. their sulfatide content, and inparticular ensures a proper functioning of nerve cells. Further,inclusion of a proper amount of molybdenum delays brain shrinkage inpart of the elderly during aging. The present method preferablycomprises the administration of a composition comprising 0.1-100microgram molybdenum per 100 ml, preferably 1-50 μg molybdenum per 100ml.

Zinc

It is also preferred to include additional zinc into the product whichcomprises the lipids or nucleotide fraction as described above, in orderto stabilize proteins in the brain and prevent agglomeration thereof,which could impart daily life activities. The present method preferablycomprises the administration of a composition comprising 0.05 mg-25 mgzinc per 100 ml, preferably 0.1-10 mg zinc per 100 ml.

Selenium

The present composition preferably contain selenium. The antioxidantactivity of selenium advantageously prevents and/or inhibits damaged tothe brain areas which enable activities of daily living. A low seleniumlevels increases the risk for hospitalisation, particularly in elderlyand patients suffering from Alzheimer's disease. Preferably the presentmethod provides the administration of a composition comprising 0.01 and5 mg selenium per 100 ml liquid product, preferably 0.02 and 0.1 mgselenium per 100 ml liquid product. The amount of selenium administeredper day is preferably more than 0.01 mg, more preferably 0.01-0.5 mg.

Product

The present composition is preferably a ready-to-use liquid, solid, orsemi-liquid product. It can also be in a concentrated form suitable fordissolving or dilution or suitable for the purpose of fortifying asecond product. The preparation can be a drink, an emulsion, adispersion, a pill or capsule, a bar, a powder, granulated or not, apudding, a sauce, a gel, an ice cream, a soup, a cookie, a lollipop,sweetie, or other form known in the art. The present composition ispreferably enterally administered, more preferably orally. Mostpreferably the present composition is administered through a straw.

The subjects that can benefit from the method and composition of theinvention (particularly patients suffering from Alzheimer's, dementiaand/or elderly) often experience problems with eating. Their sensorycapabilities and/or control of muscles has become imparted, as well asin some instances their ambition to apply proper eating habits.Swallowing and/or mastication are often problematic. The presentinvention therefore preferably has a low viscosity, preferably aviscosity between 1 and 2000 mPa·s measured at a shear rate of 100 sec⁻¹at 20° C. More preferably, the present composition is preferablyprovided in the form of a drink capable of being ingested through astraw which makes the product even easier to ingest and improvescompliance. In a preferred embodiment the present composition has aviscosity of 1-80 mPas at a shear rate of 100 per sec at 20° C., morepreferably of 1-40 mPas at a shear rate of 100 per sec at 20° C. To beoptimally accepted by the patient, the present composition preferablyhas an osmolality of 300 to 800 mOsm/kg.

Additionally many of the subjects (e.g. suffering from Alzheimer's,dementia and/or elderly) experience a general loss in appetite and/orbecome malnourished. Hence it is advantageous to include within thepresent composition other nutrients. However, the energy density of theproduct is preferably not so high that it interferes with normal eatinghabits. When in liquid form, the present product preferably containsbetween 0.2 and 3 kcal/ml, more preferably between 0.5 and 2, between0.7 and 1.5 kcal/mL

Advantageously the present composition contains digestiblecarbohydrates. The digestible carbohydrates positively influence theoperational skills of the subject, and have an advantageous effect overand above the effects for the present composition containing LCP and/oruridine. The present composition preferably contains between 1 and 50gram digestible carbohydrates per 100 ml of a liquid product, morepreferably between 5 and 30 grams per 100 ml, more preferably 10-30grams carbohydrates/100 ml. The total amount of digestible carbohydratesis preferably between 25 and 80 wt. % on dry matter, preferably 40-80wt. % based on dry matter.

The product is mainly administered to frail elderly, wherein musclestrength is preferably improved. The present composition preferablycontains protein to improve muscle strength. The improved musclestrength provides an important stimulus for support of activities ofdaily living, and advantageously contributes to the present method. Thepresent composition preferably contains 0.5-15 gram protein per 100 mlof the liquid product, preferably 1-10 grams per 100 ml of the liquidproduct, more preferably 1-5 grams per 100 ml of the liquid product.Preferably the present composition contains at least 80 wt. % milkderived protein (e.g. whey and/or casein) based on total protein.

The present method preferably comprises the administration of acomposition of 50 to 250 ml, preferably 75 to 150 ml.

Subjects

The present composition is preferably administered to a human, morepreferably to (i) an elderly human (dementing or non-dementing) and/or ahuman suffering from Alzheimer's disease, (senile) dementia, Parkinson'sDisease, Multiple Sclerosis, aphasia, apraxia, ataxia, dystonia ordyskinesia. In this respect, it is submitted that in the context of thisapplication, an elderly person is a person of the age of 50 or more, inparticular of the age of 55 or more, more in particular of the age of 60or more, more in particular of the age of 65 or more. This rather broaddefinition takes into account the fact that the average age variesbetween different populations, on different continents, etc. Mostdeveloped world countries have accepted the chronological age of 65years as a definition of “elderly” or older person (associated with theage at which one may begin to receive pension benefits), but like manywesternized concepts, this does not adapt well to e.g. the situation inAfrica. At the moment, there is no United Nations (UN) standardnumerical criterion, but the UN agreed cut-off is 60+ years to refer tothe older population in Western world. The more traditional Africandefinitions of an elder or “elderly” person correlate with thechronological ages of 50 to 65 years, depending on the setting, theregion and the country.

The present method is particularly suitable for patients suffering fromAlzheimer's disease and/or MCI. Preferably, the present composition isadministered to a subject suffering from Alzheimer's, more preferably asubject suffering from early or mild Alzheimer's, preferably to asubject suffering from Alzheimer's disease, wherein said subject with amini mental state examination (MMSE) score of 16 to 27, preferably 20 to26. It was found that in this subgroup of Alzheimer patients the presentcomposition was particularly effective. This patient group is often onthe edge of loosing independence on the activities of daily living.Hence, restoring and improving the present skills of this group ofpatients have a particularly high benefit. The present method is alsosuitable for dementing and non-dementing elderly, in particularnon-dementing elderly, for the same reasons as given above.

Uses

The present method particularly aims to (i) support and/or enhance theactivities of daily living and/or prolonged independent living.

The term “activities of daily living” as used in the present inventionrelates to instrumental and/or basic activities of daily living. Inparticular the present invention provides a method for supporting and/orenhancing the instrumental and/or basic activities of daily living.Preferably at least one of the following instrumental activities ofdaily living is supported and/or enhanced: performing light and/or heavyhousework, preparing meals and/or drinks, shopping for groceries, usinghousehold appliances (particularly the telephone) and taking medication.Preferably at least one of the following basic activities of dailyliving is supported or enhanced: personal hygiene activities(particularly washing and/or bathing), dressing, walking and/or usingthe toilet.

“Prolonging independent living” as used in the present invention can beeasily determined by tests which determine the effect of a therapy onthe time before the patient is moving to an institution. The presentinvention also relates to a method for increasing the time to nursinghome admission, comprising administering the present composition. Afurther benefit of the present invention is a reduced caregiver burden.

In one aspect the present invention provides for a method (or use) ofthe present composition for improving the ability to/for: (i) eating,walking, toileting, bathing, grooming and/or dressing; and/or (ii) useof communication equipment (particularly telephone), makingconversations, keeping appointments, use of household appliances(particularly television), cleaning dishes, preparation of meal ordrink, writing, reading, independent housekeeping, transportation and/orshopping. Typically, the method of the invention aims at supporting orimproving the capability of performing practical operations which morerely on motor capacities than on cognitive capacities. The method of theinvention thus serves at improving quality of life.

The activities of daily living also include the power or capability tomake rapid or secure movements, or to walk safely or without feelings offear of falling on the ground or to maintain equilibrium of the bodyunder those conditions that for young healthy persons give no problem.The support of these activities in persons in need of such supportresult in a maintenance, a restoration or a decrease in the decline ofthe capabilities to go out walking safely, to go shopping, walk timelyto the bathroom or climb the stairs.

Other activities of daily living include sensory-motor skills, whoseadequate presence becomes evident in the capability to coordinatemovements of muscles or limbs, in particular during eating or drinking,while wanting to grasp goods, or while aiming to put things on an exactlocation or in a particular position. Support of these activities inpersons in need of such support, is meant to be the maintenance,restoration or a decrease in the rate of decline of the capabilities toprepare or consume a meal, a drink.

The activities of daily life also include the capability to feel,notify, touch or clean all areas of the body. Support of theseactivities in persons in need of such support is meant to be arestoration, maintenance or decrease of the decline of feeling or fullsensation of all parts of the body, of cleaning practices and of theapplication of hygienic practices of the person's own body and theperson's environment.

Such support of the activities as occur in normal daily life, to a levelwhich keeps the persons in a state of independency and/or selfmaintenance in the society, can be achieved by administration of aneffective amount of the present composition.

The improvement of the activities of daily living can be measured.Activities of daily living can be measured using a number of tests,among which the Alzheimer's Disease Cooperative Study Activities ofDaily Living Inventory (ADCS-ADL). This is a caregiver ratedquestionnaire of 23 items, with possible scores over a range of 0-78,where 78 implies full functioning with no impairment (see: Galasko, D;Bennett, D.; Sano, M.; Ernesto, C.; Thomas, R.; Grundman, M.; Ferris,S.; and the ADCS. An Inventory to Assess Activities of Daily Living forClinical Trials in Alzheimer's Disease. Alzheimer's Disease andAssociated Disorders, 1997. Volume 11(2): S33-S39). The questionsrelative in particular to eating (1); walking (2); toileting (3);bathing (4); grooming (5); selecting clothes and dressing (6); makingtelephone calls (7); watching television (8); making conversation (9);clearing dishes from a table (10); finding personal belongings (11);getting or preparing a beverage (12); preparing a meal or snack (13);disposing of garbage or litter (14); travelling (15); shopping (16);keeping appointments or meetings (17); being alone (18); talking aboutcurrent events (19); reading (20); writing (21); pastime, hobby or game(22), and using household appliances (23). This test was used in theclinical test of Example 5.

In one embodiment the present invention provides the present compositiontogether with instructions for (preferably oral) administration of thecomposition and indication that said product can be used for one or moreof (i) supporting the activities of daily living and/or prolongindependent living; or (ii) stimulating eating, walking, toileting,bathing, grooming and/or dressing; or (iii) stimulating use ofcommunication equipment (particularly telephone), making conversations,keeping appointments, use of household appliances (particularlytelevision), cleaning dishes, preparation of meal or drink, writing,reading, independent housekeeping, transportation and/or shopping

In a further embodiment present invention provides the presentcomposition together with instructions for (preferably oral)administration of the composition and indication that administration ofthe present composition provides the health benefit as described in apublished scientific paper, said scientific paper describing a positiveoutcome for one or more of (i) supporting the activities of daily livingand/or prolong independent living; or (ii) stimulating eating, walking,toileting, bathing, grooming and/or dressing; or (iii) stimulating useof communication equipment (particularly telephone), makingconversations, keeping appointments, use of household appliances(particularly television), cleaning dishes, preparation of meal ordrink, writing, reading, independent housekeeping, transportation and/orshopping

EXAMPLES Example 1 In-Vivo Study

Rats can be modelled for the capacity to deal with difficulties ininstrumental and/or basic activities of daily living by infusing therats with beta-amyloid, a protein causing toxicity in the brain leadingto neuropathies, into the lateral ventricle of the brain. Rats infusedthis way show impairment in spontaneous activity in a new environment,which is an important part of activities of daily living, and indicativefor the instrumental and/or basic activities of daily living in humans,particularly humans suffering from Alzheimer's disease. The infused ratsdo not explore the new environment as extensively as control rats do,which is reflected in reduced exploration time and a decrease in walkingdistance. This study uses a dietary composition (diet B) to overcome thedifficulties in daily life activities.

Experimental Design

Four groups of rats received either an infusion into the lateralventricle with beta-amyloid (Abeta) or a saline solution (Sham). Fiveweeks prior to the infusions the rats were fed one of two diets, A or B.The four groups are summarized in table 1. Table 2 lists the dietarycomposition of the two diets. Diet A serves as a control diet. Diet B isenriched in e.g. DHA, uridine and choline. The rats are placed in a newenvironment (circular arena, 120 cm in diameter) for 15 minutes andtheir walking pattern is analysed.

TABLE 1 Groups of rats differing in infusion solutions and diet. GroupInfusion Diet 1 Sham A 2 Abeta A 3 Sham B 4 Abeta B

TABLE 2 Composition of the diets. Diet A Diet B g/100 g fat g/100 g fatFatty LA 31.1 30.0 Acids ALA 1.3 2.9 EPA — — DHA — 3.3 total ω-6 31.130.4 total ω-3 1.3 13.0 ω-6/ω-3 23.5 2.3 mg/100 g food mg/100 g foodPhos- Soya Lecithin — 500 pho- of which PC — 130 lipids of which PS — 20g/100 g food g/100 g food Choline — 0.95 UMP — 1.55 mg/100 g food mg/100g food Vitamins A 400 400 D3 100 100 E 3 253 K3 0.005 0.005 B1 0.4 0.4B2 0.3 0.3 B6 0.6 4.725 B12 0.005 0.00575 Vitamin C 0 200 Niacin 2 2Pantothenic acid 0.8 0.8 Choline 86.8 86.8 Folic acid 0.1 1.35 Biotin0.2 0.2 Minerals Iron 3.5 3.5 Copper 0.4 0.4 Zinc 1.2 1.2 Manganese 5 5Iodide 0.015 0.015 Selenium 0.009 0.159 Cobalt 0 0 Chromium 0.029 0.029Nickel 0.007 0.007 Fluorine 0.09 0.09 Tin 0.1 0.1 Vanadium 0.009 0.009

Results

On the control diet (A) rats infused with abeta show decreased walkingdistance in the new environment. When fed the experimental diet (B) toabeta infused rats restored exploration of the new environment to levelsof control rats (Sham operated rats, no abeta infusion). FIG. 1 showsthat Abeta infused rats displayed ˜25% reduced locomotor activity in theOpen Field on diet A diet, but not in animals on diet B.

Lateral ventricle infusions of abeta induce a reduction in activity.These effects were completely diminished by feeding the presenttreatment diet. The beneficial effects are indicative for theadvantageous used of the present composition in the present method,particularly for improving instrumental and/or basic activities of dailyliving.

Example 2 Compositions with Package

Packaged composition comprising per 125 ml:

-   Energy 125 kcal; Protein 3.9 g; Carbohydrate 16.5 g; Fat 4.9 g.-   Fat includes 1.5 g DHA+EPA, and 106 mg phospholipids (soy lecithin);    Choline 400 mg; UMP (uridine monophosphate) 625 mg; Vitamin E 40 mg    α-TE; Vitamin C 80 mg; Selenium 60 μg; Vitamin B12 3 μg; Vitamin B6    1 mg; Folic acid 400 μg.-   Minerals and trace elements: Sodium 125 mg; Potassium 187.5 mg;    Chloride 156.3 mg; Calcium 100 mg; Phosphorus 87.5 mg; Magnesium 25    mg; Iron 2 mg; Zinc 1.5 mg; Copper 225 μg; Manganese 0.41 mg;    Molybdenum 12.5 μg; Chromium 8.4 μg; Iodine 16.3 μg.-   Vitamins: Vit. A 200 μg-RE; vit. D3 0.9 μg; vit. K 6.6 μg; Thiamin    (B1) 0.19 mg; Riboflavin (B2) 0.2 mg; Niacin (B3) 2.25 mg-NE;    Pantothenic acid (B5) 0.66 mg; Biotin 5 μg.

The package indicates that the composition improves the activities ofdaily living, particularly stimulating independent walking, bathing,grooming, dressing, use of communication equipment (particularlytelephone), use of household appliances (particularly television),cleaning dishes, preparation of meal or drink and/or writing. Thecomposition is suitable for administration to patients suffering fromdementia or Alzheimer's disease.

Example 3 In Vivo Study

Rats were fed diets specific in B-vitamins (vitamin B₆, vitamin B₁₂, andfolic acid) content during four weeks. One group was fed a dietdeficient of B vitamins and the other group was fed a B-vitamin enricheddiet. The rats were housed in groups of four and locomotor activity wasassessed in the home cages. The average percentage of the change inactivity between the four week intervention period and a control periodwas calculated.

During the sleep (inactive) period, the average change in activity wasdecreased in rats fed the B-vitamin enriched diet as compared to theB-vitamin deficient diet (p=0.046). In fact, the locomotor activityincreased in the rats fed the B-vitamin deficient diet, while itdecreased in the rats fed the B-vitamin enriched diet as compared to thecontrol period. Locomotor activity was increased during the sleep periodof the rat by feeding a B-vitamin deficient diet. In contrast, activityduring the sleep period was decreased by feeding B-vitamin enricheddiet. This indicates that rats show a disturbed sleeping pattern when aB-vitamin deficiency is induced. Hence, wellbeing is affected by theB-vitamin deficient diet, as a disturbed sleeping pattern most likelydecreases wellbeing. In contrast, wellbeing was improved in rats fed theB-vitamin enriched diet: locomotor activity was decreased and thereforetime spent at rest increased.

Example 5 Clinical Study

The present study was performed to assess the effect of an interventionwith a medical food on activities of daily living in Alzheimer's Disease(AD) subjects. 212 subjects were randomly allocated in a double-blind 12weeks study to receive a 125 ml (125 kcal) once-a-day milk-based drinkwith: (a) the formula according to Example 2 (active product) or (b) aniso-caloric control drink (control product) according to Example 2, butwithout EPA, DHA, phospholipids, choline, UMP, vitamin E, vitamin C,selenium, vitamin B12, vitamin B6 and folic acid. Outcome measure was anADCS-ADL Inventory (Alzheimer's Disease Cooperative Study-Activities ofDaily Living).

Activities of daily living were measured using the Alzheimer's DiseaseCooperative Study Activities of Daily Living Inventory (ADCS-ADL). Thisis a caregiver rated questionnaire of 23 items, with possible scoresover a range of 0-78, where 78 implies full functioning with noimpairment. The ADCS-ADL assesses functional capacity across a widespectrum of severity and was the primary tool for collecting ADL datafor this study population.

Results:

At baseline, there was no significant difference between the grouptreated with the active product and the group treated with the controlproduct. However, there was a significant difference between the twogroups in the increase in ADCS-ADL score over the 12 weeks interventionperiod (p=0.024). The control group (n=106) had an average improvementof +0.72 points, whereas the active group (n=106) had an averageimprovement of +1.85 points on the ADCS-ADL scale (FIG. 2).

The improved ADCS-ADL score over 12 weeks was mainly the result of animprovement in instrumental activities.

This study demonstrates that intervention with the active product ofExample 2 for 12 weeks improves activities of daily living.

What is claimed:
 1. A method for supporting activities of daily livingof a subject suffering from Alzheimer's disease or dementia and/ordementing elderly comprising administering to said subject or elderly acomposition comprising: (a) DHA and/or EPA, and (b) uridine, or itsequivalent.
 2. A method for supporting activities of daily living ofnon-dementing elderly comprising administering to said elderly acomposition comprising: (a) DHA and/or EPA, and (b) uridine, or itsequivalent.
 3. The method according to claim 1, wherein the activitiesof daily living are measured using the Alzheimer's Disease CooperativeStudy Activities of Daily Living Inventory (ADCS-ADL).
 4. The methodaccording to claim 1, wherein the subject is a human suffering fromAlzheimer's disease and having a mini mental state examination (MMSE)score between 16 and
 27. 5. The method according to claim 1, wherein thecomposition further comprises folic acid, vitamin B12, vitamin B6, or acombination thereof.
 6. The method according to claim 1, wherein theactivities comprise the ability for: eating, walking, toileting,bathing, grooming or dressing; or use of communication equipment, makingconversations, keeping appointments, use of household appliances,cleaning dishes, preparation of meal or drink, writing, reading,independent housekeeping, transportation or shopping.
 7. The methodaccording to claim 1, wherein the composition comprises 0.1-2 g uridine,calculated as uridine monophosphate, per daily dosage unit.
 8. Themethod according to claim 1, wherein the composition comprises 300-3600mg DHA per daily dosage unit.
 9. The method according to claim 1,wherein the composition further comprises arachidonic acid (AA).
 10. Themethod according to claim 9, wherein the composition has a DHA to AAweight ratio of at least 2.0.
 11. The method according to claim 1,wherein the composition is a liquid with a viscosity of 1-40 mPa·smeasured at a shear rate of 100 per sec at 20° C.
 12. The methodaccording to claim 1, wherein the composition further comprises 80-2000mg choline per daily dosage unit.
 13. A liquid composition comprisingper 100 ml: (a) 0.2-2 gram uridine or an uridine equivalent; (b) 0.5-5 gDHA; (c) 0.5-10 g protein; (d) 2-20 g carbohydrates; (e) 0.5-15 μgvitamin B12; (f) 50-1000 μg folic acid; and (g) 0.1-10 mg vitamin B6,wherein the composition has a viscosity of 1-40 mPas measured at a shearrate of 100 per sec at 20° C.; an osmolality of 300 to 800 mOsm/kg; anda caloric density between 0.2 and 3 kcal/ml.